Final progression-free survival, interim overall survival, and biomarker analyses of CHOICE-01: A phase 3 study of toripalimab versus placebo in combination with first-line chemotherapy for advanced NSCLC without EGFR/ALK mutations.
Authors: Jie Wang, Zhijie Wang, Lin Wu, Baolan Li, Ying Cheng, Xiaoling Li, Xicheng Wang, Liang Han, Xiaohong Wu, Yun Fan, Yan Yu, Dongqing Lv, Jianhua Shi, Jianjin Huang, Shaozhang Zhou, Baohui Han, Guogui Sun, Qisen Guo, Youxin Ji, Xiaoli Zhu
Journal: Journal of Clinical Oncology (2022)

9028 Background: Toripalimab (anti-PD-1) in combination with chemotherapy showed significant improvement in progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced NSCLC regardless of tumor PD-L1 expression. Whole exome sequencing (WES) was performed to identify correlative biomarkers for survival. Methods: Patients (n = 465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) in combination with chemotherapy for 4-6 cycles, followed by maintenance of toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Stratification factors included PD-L1 expression status, histology, and smoking status. The primary endpoint was PFS by investigator per RECIST v1.1. Secondary endpoints included PFS by a blinded independent review committee (BIRC), OS and safety. Results: At the prespecified final PFS analysis (cutoff date Oct 31, 2021), a significant improvement in PFS as assessed by investigator was observed for the toripalimab arm over the placebo arm: HR = 0.49 (95% CI: 0.39-0.61), two-sided p &lt; 0.0001, median PFS 8.4 vs 5.6 months. The 1-year PFS rates were 36.7% vs 17.2%. PFS as assessed by BIRC was also significantly longer in the toripalimab arm. The improvements of PFS were observed across key subgroups, including histology and PD-L1 expression. At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm: HR = 0.69 (95% CI: 0.52-0.92), two-sided p = 0.0099, median OS not reached vs 17.1 months. The incidence of Grade ≥3 adverse events (AEs) (78.6% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%) and fatal AEs (5.5% vs 2.6%) were more frequent in the toripalimab arm. WES results from 394 available patients revealed that patients with high tumor mutational burden (TMB) (≥10 mutations per million base pairs) were associated with significantly better PFS in the toripalimab arm over the placebo arm (median PFS 13.1 vs 5.5 months) (interaction P = 0.026). In addition, patients with mutations in the FAK-PI3K-Akt pathway or IL-7 signaling pathways achieved significantly better PFS and OS from the toripalimab chemotherapy combination (interaction P values ≤ 0.01). Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided superior PFS and OS when compared to chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1 st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411.